This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. One of the remaining enigmas in immunology is the ability of the fetus to escape rejection by the maternal immune system despite antigenic differences in the embryo contributed by paternal alleles. It is clear from studies in placental mammals, humans in particular, that the maternal immune system is "aware" of the fetal antigens as foreign. How the maternal immune system is regulated to prevent rejection of fetal, specifically placental tissues is not completely understood. A novel approach to understanding the problem of how fetal-maternal tolerance is maintained is to ask "what mechanisms appeared during mammalian evolution to adapt the immune system to tolerate an allogeneic placenta?" This question can only be answered through comparative analysis of mammalian fetal-maternal interactions. In this proposal, we are using marsupials as the alternative models of evolution of mammalian reproduction. Two species of marsupials are used in this study;the South American opossum, Monodelphis domestica, which has a simple yolk sac placenta, and the Northern brown bandicoot, Isoodon macrourus, which has a chorio-allantoic placenta, not unlike eutherian mammals such as humans and mice. These two species should provide interesting insights into how different levels of placentation affect mechanisms of fetal-maternal tolerance. This study takes advantage of the NIH funded whole genome sequence of M. domestica.